Production of aminoalkyl ethers of diaryl carbinols



Patented Dec. 4, 1951 PRODUCTION OF AMINOALKYLETHEBS OF DIARYLCARBINOLS- John W. Cusic, Skokie, IllQ, assignor to *G. D.

Searle & (30., Skokie, Ill.,"-a corporationof Illi-' nois N Drawing.Application July 2, 1947,

Serial No. 758,705

8 Claims. (CLT260-F-570) i1 This invention relates to processes forpreparing aminoalkyl ethers of diarylcarbinols. In particular it relatesto processes for preparing aminoalkyl ethers of-diarylcarbinols byreaction of an aminoalkyl halide with a diarylcarbinol in'the' presenceof alkali, according to the equation 7 7 whereinAr and Ar are arylr'adicals,iX is halogen, All; is an alkylene radical and B is anonaromatic organic amino group.

application is a continuation-inv-part of my copending application,Serial No. 505,353, filed October 7, 1943, now abandoned.

Aminoalkyl ethers of diarylcarbinols are-useful'as antispasmodic andantihistaminic agents. Hitherto they have been prepared by such methodsas reacting an aminoalkyl halideawith the'sodium derivative of adiarylcarbinol, vprepared by reacting'sodium or sodarnide in an inertsolvent with the diarylcarbinol, or reacting a diarylmethyl halidewithan aminoalkanol in the presence of an inorganic base: Both of thesegeneral methods have certain attendant disadvantages which are avoidedby'myprocessesm I have discovered that diarylcarbinols; suchasbenzohydrol, canbe condensedwith aminoalkyl halides by reaction in thepresence-of alkali with or without theaddition ofan' inert solvent. Thisprovides a convenient" synthetic approach to ethers of the desired type,since both the diarylcarbinols'and aminoalkyl halides are readilyavailable. The yields by my methods are at least as great as andgenerally greater than yields by other procedures,"beingofthe order of60-80% of theoreticaL- I have found that the relative amounts ofreagents necessary for efficient operation of'my processes can bepractically theoretical amounts: in other-words, excesses of one ormore-reagents are unnecessary and a's'a consequencemyproce dure iseconomicalas regards materials. 'For' each mole of the dia-rylcarbiiio1I prefer'to use about 1.2 moles of the aminoalkyl halide andanequivalent amount of alkali. However; my proc-' ess Works effectivelywheh'there'is 1.05 moles of the aminoalkyl halide for eachmole' ofthedbarylcarbinol. Obviouslyincreased quantities of the aminoalkyl halide andalkali may be used for a given quantity'of diarylcarbinol, but this isunnecessary and often'undesirable'. The reac"-' tidn'can be carried outinabout-zhours, although 2 t. I prefer to extend the time toapproximately 5-8 hours, and lbngerperiods are of course suitable. Thetemperature range which I have found most satisfactory is in the rangeof-85'-100 centigrade, although the reaction proceed suitably attemperatures as-low as -70 C. and' at temperatures ash-ighas'1-l0-120"C. "It is clear that at higher temperatures shorter timesare required. It is generally possibleto select a temperature and timeinterval such that the'reaction proceeds efficientlyand'gives ahighyield of a pure product uncontaminated with starting material orside products? I prefer to carry out my reaction by mixing the threereactants in suitable proportions while applying gentle'heat, However itis sometimes desirable to" use an inert solvent for carrying out thereaction; in order to make the reaction mixture moreeasily'agitated andmore nearly homogeneous. For this purpose I have found that solventssuch'asbenzene; toluene and other hydrocarbons-iboilingain the range oftemperature at which. the reaction is to be carried out are suitable;Similarly ethers and other inert substances which are stable to alkalican be i the diaryl carbinols-having the formula ctr-eon Ariand Arrepresent aryl' radicals of the .benzene series such as phenyl andsubstituted-phenyl radicals wherein the substituents are stable toalkali and'include groups such as alkyl, alkoxy, halo, nitro, aminoand-the like. Ar and Ar may represent the same or different arylradicals.

In' .the aminoalkyl y'haiide having" the formula X represents 'ahalogenatom "suchas chlorine, bromine or'iodine; For practicalconsiderations I prefer to usethe' chlorides, sincethey are moreeasi1yprepared"and' cheaper; but the bromides and iodidesare'equally"satisfactory. It i often more convenient to'use' theaminoalkyl halide hydro'ha'lideysincesuch salts are stable crystallinederivatives. When these salts are used, a greaterquantity'of alkali isof course'required to neutralize" the hydrohalic'acid. The aminogrouping B represents an aliphatic or an aliphatic-type secondaryortertiary-amino group such "asa monoor dialkylamino group or an amino*grcup"de rived "froman aliphatic-type aminesuc'h 'as piperidine',pyrrolidine, morpholine; thiamorpholine and alkylatedderivatives of suchheterocyclic amines. My process is suitable for aminoalkyl halideswherein the amino group is derived from a strong primary or secondaryorganic base, such as those having ionization constants in the range of10- to l Such amines are aliphatic or aliphatic-like in theirproperties. The alkylene radical represented by Alk is a bivalentradical derived from a saturated aliphatic hydrocarbon and isexemplified by ethylene, propylene, butylene, trimethylene,tetramethylene, and amylene groups. It may be straight or branched andit may bear certain substituents such as aromatic radicals. It may bepart of a carbocyclic system or a heterocyclic system which contain theamino radical, B.

The condensing agent for my process is one of the alkalies. Of these,the sodium, potassium and lithium hydroxides are the more generallyavailable and for this reason are the preferred agents. In practicesodium hydroxide is the condensation agent of choice, due primarily toits low cost. While hydroxides of the alkali metals are the more commonof the alkalies, the alcoholates of these metals are also within thepurview of my processes and are satisfactory agents for the reaction.Among such alcoholates are the alkoxides of alkali metals, such assodium methoxide, sodium ethoxide, potassium ethoxide, potassiumtertiary-butoxide, potassium tertiaryamyloxide, sodium isopropoxide,sodium butoxide, lithium methoxide and ethoxide, and lithiumisobutoxide.

My invention is further disclosed by the following examples, whichillustrate methods of executing my process. It is obvious that thoseskilled in the art may introduce modifications in temperature, time,solvent, relative quantities of reagents and the like, without departingfrom the spirit or scope of my invention. In these examples the partsare parts by weight.

Example 1 36.8 grams of benzohydrol, 34.6 g. of beta-diethylaminoethylchloride hydrochloride and 32 g. of powdered sodium hydroxide are wellmixed and heated upon a steam bath for 8-10 hours. The melted product isthen poured into water, acidified, and the acid solution extracted withether to remove unreactedmaterials. The aqueous acid solution is thenmade strongly alkaline with sodium hydroxide, and the desired aminoalkylether extracted with ether and dried. The amino-ether thus obtained isan oil which boils at 174-176 C. at 7 millimeters pressure.

Example 2 Example 3 An intimate mixture of 184 parts of benzohydrol, 120parts of powdered sodium hydroxide and 191 parts ofbeta-di-n-butylaminoethyl chloride are heated together at 90-100" C. for8 hours.

4 Benzohydryl beta-di-n-butylaminoethyl ether is isolated as in Example2 and distils at 188-190 C. at 6 mm.

Example 4 184 parts of benzohydrol, 149 parts of gammadiethylaminopropylchloride and parts of powdered sodium hydroxide are thoroughly mixed andheated at -100 C. for 10 hours with occasional agitation. The base isisolated as in Example 2. Benzohydryl gamma-diethylaminopropyl ether soprepared distils at 172-174 C. at 6 mm. Yield, 190 parts.

Example 5 1 mole of benzohydrol, 1.2 moles of betamethylaminoethylbromide hydrobromide and 2.4 moles of powdered potassium hydroxide areintimately mixed and heated at 90-l00 C. for 6 hours. The cooled mass istaken up in an excess of dilute mineral acid and washed with benzene.The acid solution is made alkaline and the base removed with ether. Theether solution is washed with water, dried with pellets of caustic sodaand filtered. The filtrate is treated with a slight excess of anhydrousalcoholic hydrogen chloride and. the precipitate ofbeta-methylaminoethyl benzohydryl ether hydrochloride so obtained isremoved and recrystallized from isopropanol. It melts at l59-l60 C.

Example 6 A suspension of 67 parts .of beta-piperidinoethyl chloridehydrochloride, 40 parts of powdered sodium hydroxide, and 55 parts ofbenzohydrol in 500 cc. of toluene is refluxed and stirred for 5 hours.The mixture is filtered and evaporated under reduced pressure. There isobtained by this procedure beta-piperidinoethyl benzohydryl ether as anoily residue. This is taken up in ether and reacted with alcoholichydrogen chloride. The hydrochloride so prepared melts at 168-169 C.when recrystallized from isopropanol.

Example 7 199 parts of p-aminobenzohydrol, 270 parts ofbeta-diethylaminoethyl chloride and 224 parts of powdered potassiumhydroxide are thoroughly mixed and heated together at about C. for 8-10hours. The mass is leached with ether. The ether solution is washed withwater, dried and evaporated. The residue of beta-diethylaminoethylp-aminobenzohydryl ether is distilled at 245-250 C. at 5 mm. pressure.

Example 8 o,p'-Dimethylbenzohydrol (melting point 103- 105 C.) isprepared by the reaction of o-tolylmagnesium bromide (made from parts ofmagnesium and 855 parts of o-bromotoluene in dry ether) with 60 parts ofp-tolualdehyde in 3500 parts of dry ether. Then 212 parts of o,p'-dimethylbenzohydrol, 270 parts of beta-diethylaminoethyl chloride and200 parts of powdered caustic soda are intimately mixed and heated to90-l00 C. for 8 hours. The charge is leached with ether and the ethersolution is washed, dried and evaporated. beta-Diethylaminoethyl o,p'-dimethylbenzohydryl ether so obtained distils at -184" C. at 5 mm.pressure. Its hydrochloride melts at 172-174 C.

Example 9 I ride. The mixture is agitated and 180 parts of flake causticsoda is added in minutes. The charge is agitated and heated to 72 C. for/g hour, and then at 90-110 C. for 1 hours. The toluene suspension isfiltered to remove salt and the filtrate is extracted with dilutemineral acid. The acid extract is made slightly alkaline with causticsoda solution and the oily layer of betadimethylaminoethyl benzohydrylether is taken up in toluene. The toluene layer is separated, dried andevaporated. The residue distils at 156-163 C. at 1.0-1.9 mm.

Example 10 1 mole of benzohydrol is melted and mixed with 2.1 moles offlake sodium hydroxide. To the warm mixture are added in 1 hour 1.05moles of beta-dimethylaminoethyl chloride hydrochloride. The charge iskept at 70-75 C. throughout the addition and for 4 hours longer. Avolume of water approximately equal to that of the charge is added, themixture is agitated and cooled, and the aqueous layer removed. The

wherein Z and Z are members of the group consisting of hydrogen, NHz andlower alkyl radicals, in the presence of caustic alkali.

CH-OH 2. The process of preparing an aminoalkyl ether of adiarylcarbinol which comprises heating a dialkylaminoalkyl halide of theformula wherein X is halogen, All: is a lower alkylene radical and R andR are lower alkyl radicals, with a diarylcarbinol of the formula CHI-OH.4

wherein Ar and Ar are monocyclic aromatic hydrocarbon radicals, in thepresence of caustic 3. The process of producing p-dimethylaminoethylbenzohydryl ether which comprises heating at a temperature in the rangeof about C. to about 120 C. a mixture comprising about 1 to 1.2molecular equivalents of p-dimethylaminoethyl chloride and about 1 to1.2 molecular equivalents of sodium hydroxide for each equivalent ofbenzohydrol, and isolating the B-dime'thylaminoethyl benzohydryl etherthus formed.

4. The process of producing p-dimethylaminoethyl benzohydryl ether whichcomprises heating at approximately C. a mixture of equivalent amounts offi-dimethylaminoethyl chloride and benzhydrol with approximately 1.05equivalents of sodium hydroxide, and isolating the ,B-dimethylaminoethylbenzohydryl ether thus formed.

5. The process of preparing a dialkylaminoalkyl ether of benzohydrolwhich comprises heating at a temperature in the range of about 65 C. toabout C. a mixture comprising 1 to 1.2 molecular equivalents of adi(lower alkyl)amino-lower-alkyl halide, '1 to 1.2 molecular equivalentsof benzohydrol and 1 to 1.2 molecular equivalents of caustic alkali, andisolating the dialkylaminoalkyl benzohydryl ether thus formed.

6. The process of preparing a dialkylaminoalkyl ether of benzohydrolwhich comprises heating a di(lower alkyDamino-lower-alkyl halide withbenzohydrol in the presence of caustic alkali.

7. The process of preparing a beta-dimethylaminoethyl ether ofbenzohydrol which comprises heating a beta-dimethylaminoethyl halidewith benzohydrol in the presence of caustic alkali.

8. The process of preparing the beta-dimethylaminoethyl ether ofbenzohydrol which comprises heating beta-dimethylaminoethyl chloridewith benzohydrol in the presence of sodium hydroxide.

JOHN W. CUSIC.

REFERENCES CITED The following references are of record in the file ofthis patent:

UNITED STATES PATENTS Wiley and Sons, New York, 1938, pp. 83-84.

Holleman: Textbook of Organic Chem," J. Wiley and Sons, New York, 1907,pp. 371-372.

Fieser et al.: Organic Chemistry, Heath and 00., Boston, Mass, 1944, pp.127-128.

1. THE PROCESS OF PREPARING AN AMINOALKYL ETHER OF A DIARYLCARBINOLWHICH COMPRISES HEATING AN AMINOALKYL HALIDE OF THE FORMULA @SP X-ALK-B@SP WHEREIN X IS HALOGEN, ALK IS A LOWER ALKYLENE RADICAL AND B IS ANAMINO RADICAL SELECTED FROM DI(LOWER ALKYL) AMINO, MONO(LOWERALKYL)AMINO AND 1-PIPERIDINO RADICALS, WITH A DIARYLCARBINOL OF THEFORMULA